Postnatal confirmation of prenatally diagnosed trisomy 20 mosaicism in a patient with linear and whorled nevoid hypermelanosis

Linear and whorled nevoid hypermelanosis (LWNH) is characterized by hyperpigmented reticulate macules in a Blaschko linear arrangement without atrophy or preceding inflammation. Underlying chromosomal mosaicism was often assumed, but has been verified in only a few published cases. We report a 7-year-old boy with LWNH associated with congenital ventricular septal defect and psychomotor retardation. Prenatal chromosomal analysis of amniocytes revealed trisomy 20 mosaicism, which was not confirmed in peripheral blood lymphocytes after birth. Histologic sections of skin biopsy specimens taken at age 6 years showed hyperpigmentation of the basal epidermal layer with prominent melanocytes and isolated melanophages in the upper dermis. Cytogenetic analysis of cultured skin fibroblasts revealed an extra chromosome 20 in 5 of the 30 metaphases studied (17%). Mosaic trisomy 20 is one of the most common autosomal mosaicisms identified in amniocytes and is, as a rule, compatible with normal pregnancy outcome. In postnatal analysis of peripheral blood lymphocytes, an extra chromosome 20 could never be detected. However, when confirmed in skin fibroblasts, trisomy 20 mosaicism may be associated with systemic anomalies. The present case shows for the first time an association of LWNH with trisomy 20 mosaicism and emphasizes the importance of analyzing skin fibroblasts in cases of prenatally diagnosed trisomy 20.     

Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency.

The cholesteryl ester transfer protein (CETP) transfers lipids among lipoprotein particles and plays a central role in lipoprotein metabolism. Humans with genetic deficiency of CETP have both elevated HDL cholesterol and apolipoprotein A-I concentrations as well as decreased LDL cholesterol and apolipoprotein B levels. The present study was undertaken to elucidate the metabolic basis for the decreased LDL cholesterol and apo B levels in CETP deficiency. We conducted a series of in vivo apo B kinetic studies in tow unrelated homozygotes with CETP deficiency and in control subjects. A primed constant infusion of stable isotopically labeled phenylalanine was administered to the two CETP deficient subjects and control subjects and apo B kinetic parameters in VLDL, intermediate density lipoproteins, and LDL were obtained by using a multicompartmental model. The fractional catabolic rates (FCR) of LDL apo B were significantly increased in the CETP-deficient subjects (0.56 and 0.75/d) compared with the controls (mean FCR of 0.39/d). Furthermore, the production rates of apo B in VLDL and intermediate density lipoprotein were decreased by 55% and 81%, respectively, in CETP deficiency compared with the controls. In conclusion, CETP-deficient subjects were demonstrated to have substantially increased catabolic rates of LDL apo B as the primary metabolic basis for the low plasma levels of LDL apo B. This result indicates that the LDL receptor pathway may be up-regulated in CETP deficiency.     

IgG4-related Disease with a Cardiac Mass Causing Cerebral Infarction

Immunoglobulin G4-related disease (IgG4-RD) is a systemic inflammatory disease characterized by infiltration of extensive IgG4-positive plasma cells and lymphocytes. Although IgG4-RD has been observed in almost all organs, it rarely affects the myocardium. Cardiovascular lesions of IgG4-RD appear as aortic (aortic aneurysm and aortitis) and pericardial (constrictive pericarditis) lesions as well as pseudotumors around the coronary arteries. We herein report a case of IgG4-RD with a cardiac mass in the right atrium involving a sinus node. This condition caused arrhythmia and repeated strokes. We successfully treated the patient through resection of the cardiac mass, catheter ablation and immunosuppressive therapy.     

Adiponectin is independently associated with insulin sensitivity in women with polycystic ovary syndrome

OBJECTIVE: The polycystic ovary syndrome (PCOS) is associated with obesity and insulin resistance predisposing to diabetes mellitus type 2 and atherosclerosis. Adiponectin is a recently discovered adipocytokine with insulin-sensitizing and putative antiatherosclerotic properties. The aim of the study was to elucidate determinants of circulating adiponectin levels and to investigate the potential role of adiponectin in insulin resistance in PCOS women. PATIENTS AND MEASUREMENTS: Plasma adiponectin and parameters of obesity, insulin resistance and hyperandrogenism were measured In 62 women with PCOS and in 35 healthy female controls. RESULTS: Both in PCOS and controls, adiponectin levels were lower in overweight or obese women than in normal-weight women, without any difference between PCOS and controls after adjustment for body mass index (BMI). In PCOS and in controls there was a significant correlation of adiponectin with BMI (r = -0.516, P < 0.001), fasting insulin (r = -0.404, P < 0.001), homeostasis model sensitivity (HOMA %S) (r = -0.424, P < 0.001) and testosterone (r = -0.279, P < 0.01), but no correlation with androstenedione (r = -0.112, P = 0.325), 17-OH-progesterone (r =-0.031, P = 0.784) or the LH/FSH ratio (r =-0.033, P = 0.753). Multiple linear regression analysis revealed that BMI and HOMA %S but not testosterone were independently associated with adiponectin plasma levels, explaining 16% (BMI) and 13% (HOMA %S) of the variability of adiponectin, respectively. In PCOS patients insulin sensitivity, as indicated by continuous infusion of glucose with model assessment (CIGMA %S) was significantly correlated with adiponectin (r = 0.55; P < 0.001), BMI (r =-0.575; P < 0.001), waist-to-hip ratio (WHR) (r =-0.48; P = 0.001), body fat mass assessed by dual-energy X-ray-absorptiometry (DEXA) [Dexa-fat (total) (r = -0.61; P < 0.001) and Dexa-fat (trunk) (r = -0.59; P < 0.001)] and with testosterone (r = -0.42; P = 0.001). Multiple linear regression analysis demonstrated that markers of obesity such as BMI, total or truncal fat mass, age and adiponectin were independently associated with CIGMA %S, and that circulating adiponectin accounted for about 18% of the degree of insulin resistance in PCOS. By contrast, testosterone was not a significant factor, suggesting that PCOS per se did not affect insulin sensitivity independent from obesity, age and adiponectin. Metformin treatment for 6 months in insulin-resistant PCOS women (n = 9) had no effect on plasma adiponectin (P = 0.59) despite significant loss of weight and fat mass and improvement in hyperandrogenaemia. CONCLUSIONS: PCOS per se is not associated with decreased levels of plasma adiponectin. However, circulating adiponectin is independently associated with the degree of insulin resistance in PCOS women and may contribute to the development and/or maintenance of insulin resistance independent from adiposity.     

Inverted tandem (“mirror”) duplications in human chromosomes: Inv dup 8p, 4q, 22q

We have studied 4 patients with inverted tandem duplications of parts of chromosomes, a hitherto rarely identified from of a structural rearrangement involving a single chromosome in man. In Patients 1 and 2, the duplication involved parts of the short arm of chromosome 8 (regions 8p 12→8p23 and 8p21→8p23, respectively). Both patients manifested certain characteristics of the mosaic trisomy 8 syndrome. Elevated levels of glutathione reductase (GSR) in their erythrocytes supported the interpretation of a partial duplication of chromosome 8 and indicated a regional localization for the GSR gene locus. In Patient 3, the distal half of the long arm of chromosome 4 was duplicated (region4q26→4q35). Clinical evidence supported this interpretation, as Patient 3 resembled phenotypically the 13 reported cases with duplication of the distal 4q. The cytogenetic findings in Patient 4 suggested a possibly inverted duplication of 22q. The clinical correlation was less convincing due to the lack of a well-defined phenotype for trisomy 22. These chromosome aberrations had occurred de novo in all 4 cases. Although they involved different chromosomal regions, they might well have arisen by the same mechanism. Possible modes of origin that are discussed in detail include unequal exchange between homologous chromosomes, between chromatids of 1 chromosome or between strands of 1 DNA duplex.     

Altered reward processing in the nucleus accumbens and mesial prefrontal cortex of patients with posttraumatic stress disorder

Posttraumatic stress disorder (PTSD) is known to be associated with altered medial prefrontal activation in response to threatening stimuli and with behavioural deficits in prefrontal functions such as working memory and attention. Given the importance of these areas and processes for decision-making, this functional magnetic resonance imaging study investigated whether decision-making is altered in patients with PTSD. In particular, the neural response to gain and loss feedback was evaluated in a decision-making task in which subjects could maximise their number of points total by learning a particular response pattern. Behaviourally, controls learned the correct response pattern faster than patients. Functionally, patients and controls differed in their neural response to gains, but not in their response to losses. During the processing of gains in the late phase of learning, PTSD patients as compared to controls showed lower activation in the nucleus accumbens and the mesial PFC, critical structures in the reward pathway. This reduced activation was not due to different rates of learning, since it was similarly present in patients with unimpaired learning performance. These findings suggest that positive outcome information lost its salience for patients with PTSD. This may reflect decreasing motivation as the task progressed.     

Dimethylfumarate inhibits microglial and astrocytic inflammation by suppressing the synthesis of nitric oxide,IL-1β, TNF-α and IL-6 in an in-vitro model of brain inflammation

Background  

Brain inflammation plays a central role in multiple sclerosis (MS). Dimethylfumarate (DMF), the main ingredient of an oral formulation of fumaric acid esters with proven therapeutic efficacy in psoriasis, has recently been found to ameliorate the course of relapsing-remitting MS. Glial cells are the effector cells of neuroinflammation; however, little is known of the effect of DMF on microglia and astrocytes. The purpose of this study was to use an established in vitro model of brain inflammation to determine if DMF modulates the release of neurotoxic molecules from microglia and astrocytes, thus inhibiting glial inflammation.     

Mutational analysis using Sanger and next generation sequencing in sporadic spindle cell hemangiomas: A study of 19 cases

Spindle cell hemangioma (SCH) is a distinct vascular soft ‐ tissue lesion characterized by cavernous blood vessels and a spindle cell component mainly occurring in the distal extremities of young adults. The majority of cases harbor heterozygous mutations in IDH1/2 sporadically or rarely in association with Maffucci syndrome. However, based on mosaicism and accordingly a low percentage of lesional cells harboring a mutant allele, detection can be challenging. We tested 19 sporadic SCHs by Sanger sequencing, multiplex ligation‐dependent probe amplification (MLPA), conventional next generation sequencing (NGS), and NGS using a single molecule molecular inversion probes (smMIP) ‐ based library preparation to compare their diagnostic value. Out of 10 cases tested by Sanger sequencing and 2 analyzed using MLPA, 4 and 1, respectively, revealed a mutation in IDH1 (p.R132C). The 7 remaining negative cases and additional 6 cases were investigated using smMIP/NGS, showing hot spot mutations in IDH1 (p.R132C) (8 cases) and IDH2 (3 cases; twice p.R172S and once p.R172G, respectively). One case was negative. Owing to insufficient DNA quality and insufficient coverage, 2 cases were excluded. In total, in 16 out of 17 cases successfully tested, an IDH1/2 mutation was found. Given that IDH1/2 mutations were absent in 161 other vascular lesions tested by smMIP/NGS, the mutation can be considered as highly specific for SCH.     

Mixed hepatoblastoma in an adult

We report a case in an elderly adult of a highly malignant liver tumor with blastoid features that resembled hepatoblastoma. A liver tumor with a diameter of 23 cm was removed in a 78-year-old woman. The tumor showed highly differentiated epithelial hepatocellular and poorly differentiated epithelial and mesenchymal components. The blastoid nature and pluripotent differentiation potential were supported by immunohistologic analysis and suggest an origin of a poorly differentiated pluripotent hepatic cell with the potential to mature. We believe that this case of a mixed hepatoblastoma in an adult should be added to the growing number of presumed hepatic precursor cell neoplasms in adults.